Project Summary In December 2019, a novel coronavirus (SARS-CoV-2) emerged in the city of Wuhan, China, and quickly spread worldwide, with an increasing number of cases and deaths. In populations naive to this new pathogen, there has been immense inter-individual clinical variability among infected individuals, ranging from asymptomatic infection to lethal coronavirus infectious disease-19 (COVID-19), which is typically due to pneumonitis and rarely to encephalitis. The infection to severe/life-threatening ratio is estimated to be < 1/1,000 in people <20 years, around 5/1,000 in people 20-50 years, >1/100 over 50 years, and > 1/10 over 80 years. Underlying medical conditions also greatly increase the risk of severe COVID-19. On the other hand, rare cases of apparent resistance to the infection itself have also been identified (viral PCR-negative and seronegative individuals despite repeated and confirmed exposure). In this context, we hypothesize that monogenic inborn errors of immunity (IEI) may underlie life-threatening COVID-19 infections in previously healthy, young individuals (<50 years), whereas monogenic inborn variations of resistance (IVR) may protect other individuals from SARS-CoV- 2 infection. Both hypotheses are based on 25 years of studies of a wide range of other viral infections, for which IEI (e.g. influenza virus pneumonitis) and IVR (e.g. resistance to human immunodeficiency virus) have been identified. We will recruit both IEI and IVR cohorts not only in the USA but also, importantly, at the international level; search for candidate disease-causing variants using a cutting-edge strategy developed in our laboratory to analyze whole-exome sequencing (WES) data; and perform in-depth functional studies to characterize the products of candidate genotypes biochemically, and to analyze the corresponding patients? cells immunologically. Our program aims to discover the human genetic and immunological basis of both severe ?idiopathic? COVID- 19 and natural resistance to SARS-CoV-2. Our preliminary results are exciting. In less than 2 months, we and Helen Su (NIAID) have organized the global and growing ?COVID Human Genetic Effort? (CHGE), with over 400 collaborators and 40 sequencing hubs in 50 countries (www.covidhge.com). In the last month, our own hub sequenced over 100 patients in the IEI cohort and enrolled 2 individuals in the IVR cohort. We have already selected 5 promising candidate genes (IKFZ1, POLR3C,TLR7, IRF7, IL22), which are all involved in anti-viral interferon immunity. Our program focuses on a timely problem (severe COVID in previously healthy young patients and individuals naturally resistant to infection), tests a bold but plausible hypothesis (monogenic basis for both groups of outliers), and uses cutting-edge genetic and mechanistic studies (including the study of leukocyte subsets and induced pluripotent stem cells (iPSC)-derived pulmonary epithelial cells). Our project will permit genetic diagnosis and counseling, while facilitating the development of novel preventive and therapeutic strategies including anti-viral drugs (e.g. aimed at restoring a deficient immunity or blocking viral entry) and vaccines (e.g. aimed at boosting certain immunological pathways) in both genetic and non-genetic cases.